Table 1.
The expression pattern of membrane bound isoform of immune checkpoints (ICs) and their effects on tumor microenvironment.
| Immune Checkpoint | Cellular Expression | Ligand | Cellular Expression | Effects on Tumor Microenvironment | Ref. |
|---|---|---|---|---|---|
| CTLA-4 (CD152) | Tregs, Teffs, B cells, NK cells, NKT cells, and DCs | CD80 (B7-1), CD86 (B7-2) | APCs | Inhibits T cell activation by binding to its ligand. Inhibits IL-2 production and influences naive CD4+ T cell differentiation. | [29] |
| PD-1 | Tregs, Teffs, B cells, NK cells, mast cells, and some subsets | PD-L1 (B7-H1), PD-L2 (B7-DC) | Tumor cells, non-lymphoid, and non-hematopoietic cells | Inhibits effector T cell activation and promotes Treg cell generation | [30] |
| LAG-3 | Tregs, Teffs, B cells, NK cells, and DCs | MHC II | APCs | Has a synergistic impact with PD-1 to inhibit immune responses by suppressing T cell activation and cytokine production, thereby ensuring immune homeostasis | [31,32] |
| TIM-3 (HAVCR2) | Tregs, Teffs, NK cells, and some subsets of myeloid cells | Galectin-9, CEACAM1, Soluble HMGB1, PtdSer | Some myeloid subsets; Tregs, Teffs, NK cells, and some subsets of myeloid cells; Released by tumor cells or activated DCs: Apoptotic cells | Favors tumor escape to immune cells. Inhibits T cell responses. CD8+-T cells lose the ability to secrete cytokines IFNγ, IL-2, and TNFα |
[33,34] |
| TIGIT | Tregs, Teffs, and NK cells | CD112 (PVRL2; nectin-2), CD155 (PVR) | DCs, APCs, and tumor cells | Suppresses the activation of TILs | [35,36] |
| BTLA (CD272) | T cells, B cells, macrophages, and NK cells | HVEM, TNFRSF14 | - | Suppresses pathway for T cell, B cell, or NK. | [37,38] |
| IDO-1 | EC, fibroblasts, macrophages, DCs, and PBMCs | GITR, ICOS, CD200 | DCs | Increases intratumoral infiltration and impairs cytotoxic T cell function. In DC, decreases antigen uptake and downregulates CD40/CD80 | [39] |
APC: antigen-presenting cell; DC: dendritic cell; EC: endothelial cell; MHC: major histocompatibility complex; NK: natural killer cells; NKT: natural killer T cells; PMBCs: peripheral blood mononuclear cells; PtdSer: phosphatidylserine; Teff: effector T cells; Tregs: regulatory T cells; TILs: tumor-infiltrating lymphocytes.